The control and cure of cancer represents one of our most challenging health problems. Cancer is currently the second most common cause of death in the United States, and it is likely to become the most common cause in the near future. See, Varmus, H. The New Era in Cancer Research. Science, 2006, 312, 1162-1165. Breast cancer, the second leading cause of cancer deaths, is the most common cancer among postmenopausal women. According to the World Health Organization, more than 1.2 million people will be diagnosed with breast cancer this year worldwide, including more than 0.2 million victims in the United States. See, American Cancer Society web site. Available at: http://www.cancer.org Accessed on Aug. 18, 2006.
Chemoprevention is the use of either synthetic drugs or natural products to inhibit, reverse, or suppress the development of invasive malignant cancer, either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells in which DNA damage has already started. Chemoprevention is one of the most direct ways to reduce cancer-related morbidity and mortality. See, Hong, W. K.; Sporn, M. B. Recent Advances in Chemoprevention of Cancer. Science 1997, 278, 1073-1077.
The role of estrogens in the development of breast cancer is well established with the majority of postmenopausal women having hormone receptor-positive tumors. See, Vogel, C. L. Hormonal approaches to breast cancer treatment and prevention: an overview. Semin. Oncol. 1996, 23, 2-9; Reddy, P. A review of the newer aromatase inhibitors in the management of metastatic breast cancer. J. Clin. Pharmacol. Ther. 1998, 23, 81-90.; Tobias, J. S. Endocrine approaches for the treatment of early and advanced breast cancer in postmenopausal women. Int. J. Biochem. Cell Biol. 2004, 36, 2112-2119. One chemopreventive strategy for breast cancers is to decrease estrogen production. See, Karr, J. P.; Kaburagi, Y.; Mann, C. F. and Sandberg, A. A. The potential significance of aromatase in the etiology and treatment of prostatic disease. Steroids, 1987, 50, 449-457; Henderson, D.; Habenicht, U.-F.; Nishino, Y. and el Etreby, M. F. Estrogens and benign prostatic hyperplasia: the basis for aromatase inhibitor therapy. Steroids, 1987, 50, 219-233. Aromatase, a key cytochrome P450 enzyme, catalyzes the rate-limiting aromatization step for the conversion of androgens (testosterone and androstenedione) to estrogens (estradiol and estrone) and this pathway is the only source for estrogen in postmenopausal women. Because estrogen production is the last step in the biosynthetic sequence of steroid production, selective inhibition of aromatase would not be expected to interfere with the production of other useful steroids, such as adrenal corticoids. Thus, aromatase inhibitors have become attractive chemopreventive agents in the treatment of estrogen-dependent breast cancers. See, Attar, E. and Bulun, S. E. Aromatase inhibitors: the next generation of therapeutics for endometriosis. Fertility and Sterility, 2006, 1307-1318; Geisler, J. and Lonning, E. Aromatase inhibition: Translation into successful therapeutic approach. Clin. Cancer Res. 2005, 11, 2809-2821; Michaud, L. B., Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer. Am. J. Health-syst. Pharm, 2005, 62, 266-273; Brueggemeier, R. W.; Hackett, J. C. and Diaz-Cruz, E. S. Aromatase inhibitors in the treatment of breast cancer. Endocrine Rev. 2005, 26, 331-345; Miller, W. R. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin. Oncol. 2003, 30, 3-11; Recanatini, M.; Cavalli, A. and Valenti, P. Nonsteroidal aromatase inhibitors: recent advances. Med. Res. Rev. 2002, 22, 282-304; Kelloff, G. J.; lubet, R. A.; Lieberman, R.; Eisenhauer, K.; Steele, V. E.; Crowell, J. A.; Hawk, E. T.; Boone, C. W. and Sigman, C. C. Aromatase inhibitors as potential cancer chemopreventives. Cancer Epidemiol. Biomark. Prev. 1998, 7, 65, the disclosures of which are incorporated herein by reference.
In the last two decades, several classes of steroidal and nonsteroidal synthetic aromatase inhibitors such as aminoguletethimide and imidazole or triazole derivatives have been designed. The first FDA-approved aromatase inhibitor, aminogluthethimide, has shown some clinical benefit in breast cancer trials, but lack of selectivity and its weak aromatase inhibitory activity has limited its usefulness. Other aromatase inhibitors recently approved by the FDA include the nonsteroidals anastrazole and letrozole, as well as the steroidal exemestane that, like all aromatase inhibitors, inhibit the synthesis of estrogen in tissues other than the ovaries and also cause several severe adverse effects. See, Howell, A.; Robertson, J. F. R.; Vergote, I. A review of the efficacy of anastrozole in postmenopausal women with advanced breast cancer with visceral metastases. Breast Cancer Res. Treat. 2003, 82, 215; Scott J. Lesley and Keam J. Susan. Letrozole: In postmenopausal hormone-responsive early-stage breast cancer. Drugs 2006, 66, 353-362; Lonning, B. P. E.; Bajetta, E.; Murray, R.; Tubiana-Hulin, M.; Eisenberg, P. D.; Mickiewicz, E.; Celio, L.; Pitt, P.; Mita, M.; Aaronson, N. K.; Fowst, C.; Arkhipov, A.; Salle, E-d.; Polli, A. and Massimini, G. Activity of Exemestane in Metastatic Breast Cancer After Failure of Nonsteroidal Aromatase Inhibitors: A Phase II Trial. J. Clin. Oncol. 2000, 18, 2234-2244, the disclosures of which are incorporated herein by reference.
Besides the development of synthetic aromatase inhibitors, there is a continuing search for new classes of natural products to inhibit aromatase in order to discover novel breast cancer chemopreventive agents. In this regard, abyssinone II (7-hydroxy-2-(4-hydroxy-3-(3-methylbut-2-enyl)phenyl)chroman-4-one), a prenylated flavanone isolated from the Chinese medicinal plant Broussonetia papyafera, has shown significant inhibitory activity as its (2S) enantiomer in an aromatase assay with an IC50 of 0.37 μM observed in a radiometric method. See, Lee, D. P.; Bhat, L.; Fong, H. H. S.; Farnsworth, N. R.; Pezzuto, J. M. and Kinghorn, A. D. Aromatase inhibitors from Broussonetia papyrifera. J. Nat. Prod. 2001, 64, 1286-1293, the disclosure of which is incorporated herein by reference. Abyssinone II, therefore, has the potential to inhibit carcinogenesis, and was selected as one of the chemopreventive agents for further studies under the Rapid Access to Preventive Intervention Development (RAPID) program of the National Cancer Institute.
Several food-based chemopreventive agents have also shown promise in clinical trials. See, Decensi, A.; Serrano, D.; Bonanni, B.; Cazzaniga, M.; Guerrieri-Gonzales, A. Breast Cancer Prevention Trials Using Retinoids. J. Mammary Gland Biol. Neoplasia 2003, 8, 19-30. The medicinal value of zapote blanco, a fruit of Casimiroa edulis Llave & Lex (Rutaceae) that is consumed in many parts of the world, was first discovered by the Aztecs, and crude plant extracts of the seeds or leaves of Casimiroa edulis have been found to affect blood pressure, cardiac activity, aortic muscular tone, and to possess anticonvulsant activity. Recently, zapotin (5,6,2′,6′-tetramethoxyflavone), a polymethoxylated flavonoid isolated from zapote blanco seeds, was found to be a non-toxic inducer of cellular differentiation with cultured HL-60 promyelocytic cells. See, Mata-Greenwood, E.; Ito, A.; Westenburg, H.; Cui, B.; Mehta, R. G.; Kinghorn, A. D.; Pezzuto, J. M. Discovery of Novel Inducers of Cellular Differentiation Using HL-60 Promyelocytic Cells. Anticancer Res. 2001, 21, 1763-1770, the disclosure of which is incorporated herein by reference. Zapotin, therefore, has the potential to inhibit carcinogenesis.
The discovery of compounds specifically targeting cancer cells, or the cellular mechanisms involved in the proliferation of cancer cells, can provide significant advancement in the eradication and/or control of cancer. The limited availability of abyssinone II and zapotin from natural sources as well as from poor-yielding syntheses has hampered not only more advanced biological testing of these flavonoid compounds, but also the syntheses of various analogues the testing of which could elucidate structure-activity relationships and guide further investigation and development of new chemopreventive agents. Therefore, the development of practical syntheses of abyssinone II and zapotin would permit a more thorough evaluation of their potential as chemopreventive agents, and establish the basis for respective analogue programs.